The use of recombinant genes or growth-factors to enhance myocardial collateral blood vessel function may represent a new approach to the treatment of cardiovascular disease. Kornowski, R., et al., “Delivery strategies for therapeutic myocardial angiogenesis”, Circulation 2000; 101:454–458. Proof of concept has been demonstrated in animal models of myocardial ischemia, and clinical trials are underway. Unger, E. F., et al., “Basic fibroblast growth factor enhances myocardial collateral flow in a canine model”, Am J Physiol 1994; 266:H1588–1595; Banai, S. et al., “Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs”, Circulation 1994; 83–2189; Lazarous, D. F., et al., “Effect of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart”, Circulation 1995; 91:145–153; Lazarous, D. F., et al., “Comparative effects of basic development and the arterial response to injury”, Circulation 1996; 94:1074–1082; Giordano, F. J., et al., “Intracoronary gene transfer of fibroblast growth factor-S increases blood flow and contractile function in an ischemic region of the heart”, Nature Med 1996; 2:534–9. Most strategies for trans-catheter delivery of angiogenic factors have employed an intracoronary route which may have limitations due to imprecise localization of genes or proteins and systemic delivery to non-cardiac tissue. Thus, it would be desirable to have the capacity for direct delivery of angiogenic factors or genes to precisely defined regions of the myocardium rather than to the entire heart, and to minimize the potential for systemic exposure. Guzman, R. J., et al., “Efficient gene transfer into myocardium by direct injection of adenovirus vectors”, Circ Res 1993; 73:1202–7; Mack, C. A., et al., “Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for VEGF-121, improves myocardial perfusion and function in the ischemic porcine heart”, J Thorac Cardiovasc Surg 1998;115:168–77.
The effect of direct intra-operative intramyocardial injection of angiogenic factors on collateral function has been studied in animal models of myocardial ischemia. Open chest, transepicardial administration of an adenoviral vector containing a transgene encoding an angiogenic peptide resulted in enhanced collateral function. (Mack et al., supra.) Angiogenesis was also reported to occur with direct intramyocardial injection of an angiogenic peptide or a plasmid vector during open heart surgery in patients. Schumacher, B., et al., “Induction of neoangiogenesis in ischemic myocardium by human growth factors. First clinical results of a new treatment of coronary heart disease”, Circulation 1998; 97:645–650; Losordo, D. W., et al., “Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia”, Circulation 1998; 98:2800.
Despite the promising hope for therapeutic angiogenesis as a new modality to treat patients with coronary artery disease, there is still a huge gap regarding what specific strategy will optimally promote a clinically relevant therapeutic angiogenic response. Moreover, it is unclear which one (or more) out of multiple angiogenic growth factors may be associated with a beneficial angiogenic response. In addition, the use of different tissue delivery platforms, e.g., proteins, adenovirus, or “naked” DNA, to promote the optimal angiogenic response has remained an open issue.